In recent years, many new monoclonal antibodies have become available for defining lymphocyte subsets. As more information accumulates on how the immune system evokes characteristic responses in autoimmune inflammatory diseases, the value of these antibodies as therapeutic agents has become increasingly evident. Use of antibodies directed against the L3T4 molecule, a marker of the murine helper T cell subset, has proven to be an effective strategy in the treatment of several murine models of human autoimmune disorders: experimental allergic encephalomyelitis, a model for multiple sclerosis, NZB/W disease, a model for systemic lupus erythematosus, and type II collagen arthritis, a model for rheumatoid arthritis. In this grant application, we propose to test the feasibility of using monoclonal antibodies and immunotoxins in genetically diabetic NOD mice to 1) block the onset of insulitis and consequently block the expression of overt diabetes, and 2) block rejection of allogeneic pancreatic islets transplanted into diabetic and/or pre-diabetic NOD mice. These studies are ultimately directed towards the development of procedures for overcoming the autoimmune destruction and allograft rejection which remain the major obstacles to treatment of human Type I diabetes. Methodologies are currently available in our laboratory for the isolation of the murine monoclonal antibodies GK 1.5 and 13.4 to be used in these studies, for the production of immunotoxins using commercially available diptheria toxin, as well as the technology for islet transplantation.